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Widely prescribed drugs that inhibit cholesterol synthesis may be linked to increased autism diagnoses in children. This prompts the need for new investigation of drug safety and more cautious prescribing during pregnancy. <\/span><\/strong><\/em><\/p>\n <\/span><\/span><\/span><\/strong>Study: Sterol pathway disruption in pregnancy: a link to autism<\/a>. Image credit: Natalia Derybina\/Shutterstock.com<\/span><\/span><\/em><\/p>\n a fresh molecular psychiatry<\/strong><\/em><\/a> The study examined the association between maternal prescription of sterol biosynthesis inhibitor drugs (SBIM) during pregnancy and the risk of autism spectrum disorders (ASD) in offspring, using a large, linked maternal-child health records database.<\/p>\n Cholesterol is a fundamental component of cell membranes and is important for many molecular processes. Its biosynthesis is particularly important during embryonic development. Early in pregnancy, sterols are supplied by the mother, but by mid-gestation, the fetal brain begins to produce its own cholesterol. Disruption of this pathway due to genetic mutations or external factors can result in developmental and intellectual disorders, including Smith\u2013Lemli\u2013Opitz syndrome (SLOS), lathosterolosis, and desmosterolosis.<\/p>\n Of these disorders, SLOS has been the most extensively studied, characterized by intellectual disability and specific physical deformities. It results from a DHCR7 mutation that prevents the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol, leading to low cholesterol, excess reactive 7-DHC, and downstream cellular dysfunction.<\/p>\n Approximately 75% of people with SLOS are also diagnosed with autism spectrum disorder (ASD), and recent studies link cholesterol metabolism abnormalities to ASD in general. While increasing ASD rates are partly due to better diagnosis and broader criteria, environmental factors may also contribute. For example, maternal antidepressant use during pregnancy has been debated as a potential risk factor, particularly given the association between cholesterol balance and depression risk.<\/p>\n Common medications, such as aripiprazole or trazodone, can increase 7-DHC similar to SLOS without DHCR7 mutation. Several widely used drugs, including haloperidol, sertraline, and fluoxetine, inhibit cholesterol biosynthesis in several models. While early research has raised concerns about prenatal exposure and developmental risks, there is a significant gap in large-scale studies examining the consequences of prenatal inhibition of sterol biosynthesis.<\/p>\n A large medical record database was analyzed to determine whether exposure to SBIM is associated with risk of ASD. The current study examined both statins, which block early cholesterol synthesis, and other drugs that block later steps in the pathway.<\/p>\n <\/p>\n The data was obtained from Epic Cosmos, a de-identified dataset of 300 million patient records from more than 1,880 hospitals and 42,400 clinics, accessed between March 2025 and January 2026. The current study considered all mother-child pairs with births between January 2014 and December 2023, with follow-up through records available at least 18 months after birth and up to January 2026. Non-US births, cases of missing gender, and pregnancies exposed to valproic acid were excluded.<\/p>\n The main outcome was ASD, identified using 51 diagnostic codes. This study focused specifically on medications taken before or during pregnancy and those that block sterol biosynthesis, such as post-lanosterol pathway inhibitors (e.g., aripiprazole) and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (e.g., lovastatin, atorvastatin, simvastatin, rosuvastatin and pravastatin).<\/p>\n Patients were grouped based on the number of unique SBIMs obtained during pregnancy. Comparator drugs, which are commonly prescribed in pregnancy, but without sterol biosynthesis inhibition, include diphenhydramine, docusate, famotidine, ferrous sulfate, ondansetron, and polyethylene glycol. <\/strong>which serves as a reference to assess association specificity.<\/p>\n Sex and preterm birth (<37 weeks) were considered but not modeled, because sex is associated with ASD but not risk, whereas preterm birth may be on the causal pathway rather than acting as a confounder. Covariates included maternal age, diabetes, pre-eclampsia\/eclampsia, race, ethnicity, year of birth, urban\/rural residence, social vulnerability index, tobacco\/alcohol use in pregnancy, and pre-pregnancy body mass index (BMI).<\/p>\n The current study analyzed a nationwide cohort of more than 6 million US-born children with at least 18 months of follow-up. 11% of these mothers were given at least one drug affecting sterol biosynthesis during pregnancy, and this rate increased during the study period.<\/p>\n Children exposed to any SBIM in utero had a higher risk of ASD diagnosis than children who were not exposed. Importantly, the magnitude of this association increased when mothers were prescribed multiple SBIMs during pregnancy, with the risk increasing approximately 1.33-fold with each additional medication and the risk doubling with four or more SBIMs.<\/p>\n However, several maternal characteristics, including higher rates of metabolic and psychiatric conditions, differ between risk groups, and these underlying conditions may also contribute to ASD risk.<\/p>\n A total of 3.8% of children in the study were diagnosed with ASD, the majority of whom were exposed to SBIM in utero. After adjustment for potential confounders, some SBIMs, such as cariprazine, were associated with more than twice the observed risk of ASD compared with no exposure.<\/p>\n The association between SBIM exposure and ASD diagnosis increased rapidly with each additional SBIM determined during pregnancy, reaching more than double the baseline risk when four SBIMs were used. This pattern suggests a cumulative effect from multiple exposures. In contrast, drugs that do not affect sterol biosynthesis showed only a minimal increase in ASD risk, which was further reduced after sensitivity analysis. This supports the specificity of the association, although it does not establish causation.<\/p>\n Sensitivity analysis that accounted for maternal psychiatric diagnosis modestly reduced many of the associations, particularly for psychotropic medications, but did not eliminate the overall signal.<\/p>\n SBIM use during pregnancy was associated with an increased risk of ASD in offspring, but the observational design means causation cannot be confirmed.<\/p>\n The authors propose that these associations may reflect disruption of fetal brain development through biochemical mechanisms. Specifically, maternal exposure to SBIM may result in the accumulation of reactive oxysterols and reduced cholesterol levels, both of which have been hypothesized to adversely affect neuronal differentiation and neural circuit formation.<\/p>\n The degree of risk may be influenced by the specific SBIM agent as well as unmeasured factors such as dose, timing of exposure, and genetic predisposition, with more potent DHCR7 inhibitors causing greater concern. There is also the possibility of long-term epigenetic modifications, although these were not directly measured in this study.<\/p>\n The authors recommend that physicians reevaluate their prescribing of SBIM and closely monitor medications with sterol-inhibiting activity, including newer medications. They also recommend educating providers and patients, exploring safer alternatives, limiting multiple SBIM use during pregnancy, considering genetic risk, and supporting additional research. They caution against overinterpreting the findings and note that many of these drugs remain essential treatments, particularly outside of pregnancy, emphasizing the need to balance potential risks with clinical benefits.<\/p>\n Download your PDF copy by clicking here.<\/a><\/p>\n Journal Reference:<\/p>\nRelationship between cholesterol pathway disruption and neurodevelopment<\/h2>\n
Assessing the association between SBIM exposure and ASD risk.<\/h2>\n
Cumulative exposure to SBIM in utero increases risk of ASD in children<\/h2>\n
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